Understanding the immune response to viral infection is key to developing strategies for protection in terms of both vaccination and treatment. While some viruses are cleared completely, others such as the herpes family of viruses remain in a latent form. Exposure to Epstein Barr virus, a y-herpesvirus, during the first decade of life rarely results in clinical symptoms. Whereas infection in the second decade or later (age>15) usually leads to disease (known as infectious mononucleosls-IM), and has been correlated to increased risk for the subsequent development of autoimmune disease and certain cancers. Infectious mononucleosis is characterized clinically by fever, swollen lymph nodes, sore throat, and enlarged spleen and liver. Diagnostic blood smears show abnormal circulating cytotoxic T cells and an elevated white blood cell count. The link between cancer and Epstein Barr viral genes has been well studied but yet little is known about what factors predispose to the development of IM. Furthermore, there is no current treatment for IM and the fatigue and symptoms associated with illness results in substantial loss of productivity. The prevalent thinking in the field is that either an increased inoculating viral load or age-dependent differences in the T cell repertoire cause disease. To address these issues, a basic understanding of the viral and immunological changes that occur during primary EBV infection is needed. In this proposal, we will examine the link between the number of CD8+ T cells specific for EBV, viral load and the development of disease. We hypothesize that elevated precursor frequency and/or cross-reactive memory phenotype of EBV-specific CD8+ T cells prior to exposure determines the development of infectious mononucleosis. We also propose to develop a technique to isolate and study EBV-specific CDS T cells in adults and children prior to infection. To do this we will employ a novel technique to enrich for antigen-specific T cells using peptide MHC tetramers. Using this tool, we will determine if the number and/or phenotype of EBV-specific "naive" CDS T cells correlates with severity of subsequent disease in college students. Relevance: This proposal is consistent with multiples NIH objectives and areas of emphasis, especially immune mechanisms of viral control-NIAID. The success of new antiviral therapies is dependent on our ability to understand the interactions between viruses and the immune system. This proposal will advance the field by providing a clear understanding ofthe link between T cells and immunity to EBV and EBV related sequalae and will have implications for the optimization of not only anti-viral therapy and virus- related tumor immunity.